Aminopeptidases are a group of metalloenzymes that catalyze the hydrolysis of the NH.sub.2 -terminal peptide bonds in polypeptides. A number of effective inhibitors have been reported for aminopeptidases (A. B. Shenvi, Biochemistry 1986, 25, 1286). A number of .alpha.-aminoboronic acids (i.e. DuP 714) and their derivatives have been reported as effective inhibitors for aminopeptidases by acting as "transition-state analogues." ##STR3##
DuP 714 and its derivatives were first prepared (Wityak et al, J. Org. Chem. 1995, 60, 3717) using procedures developed by Matteson et al (J. Am. Chem. Soc. 1981, 103, 5241). The Matteson protocol is used to prepare .alpha.-amino or .alpha.-amido-boronic acids by assymetric homologation of ethylene glycol benzylboronate.
Wityak et al incorporated this technique using pinanediol 1-(3-bromopropyl)boronate (A) as the starting material to make an .alpha.-amino-boronic acid (C), which was used in the synthesis of DuP 714. Homologation occurred upon assymetric addition of (dichloromethyl)lithium to produce (B) and the chloride was displaced by nitrogen upon addition of lithiohexamethyldisilazane (KHDMS). This process uses expensive raw materials, low temperatures, and unfortunately requires difficult isolation and purification steps. ##STR4##
Hoffmann et al (Angew. Chem. Int. Ed. Engl. 1986, 25(2), 189-190) described the assymetric synthesis of .alpha.-(-chloro-(E)-crotylboronate esters via allyl rearrangement. Contacting pinacol 1-(3'-(S)-trimethylsiloxy)-butenylboronate (D) with thionyl chloride in petroleum ether formed pinacol .alpha.-chloro-(E)-crotylboronate (E) in 75% yield. Unfortunately, pinacol E cannot easily be manipulated to form a compound useful for the synthesis of DuP 714. ##STR5##
It is therefore desirable to find less expensive and simpler synthetic procedures for production of .alpha.-chloroboronic acids and their corresponding .alpha.-aminoboronic acids, which can be used as intermediates to form compounds such as DuP 714. Such procedures preferably should use readily available and inexpensive raw materials.